A macromolecule refers to a large molecule formed by polymerization of small subunits. It includes polypeptides such as polysaccharide derivatives, and polypeptide such as insulin. Some of the macromolecules such as insulin, exenatide and heparin possess biological activities and are used for therapeutic purposes.
Heparin is a mucopolysaccharide mainly composed of repeating units of D-glucosamine and L-iduronic acid. It is a component found in blood having anti-coagulant activity and has a physiological role such as anti-inflammation and inhibition of angiogenesis. Due to its numerous ionizable sulfate groups, heparin possesses a strong electronegative charge. It is also a relatively strong acid that readily forms water-soluble salts, e.g. heparin sodium. It is found in mast cells and can be extracted from many body organs, particularly those with abundant mast cells. The liver and lungs are especially rich in heparin. The circulating blood contains no heparin except after profound disruption of mast cells. Heparin has many physiological roles, such as blood anti-coagulation, inhibition of smooth muscle cell proliferation, immunesuppressive activity, and so forth. In particular, heparin is a strong anti-coagulant agent that interacts strongly with antithrombin III to prevent the formation of fibrin clots. Having these properties, heparin has been used for preventing and treating deep vein thrombosis and pulmonary embolism.
Despite of its physiological usefulness, the application of heparin has been limited due to its large molecular weight and a highly negative charge. These physical characteristics of heparin prevents its absorption through the gastrointestinal (GI) tract, nasal or buccal mucosal layers. Therefore, the only routes of administration available for clinical purposes are intravenous and subcutaneous injections.
Insulin is a macromolecule produced by Langerhans beta cells of pancreas having a distinctive physiological role. It is released from pancreas when the blood glucose level is high in body and regulates the glucose level by allowing higher absoprtion of glucose into liver, muscle, and fat tissue where excess amount of glucose is stored in the form of glycogen, and by inhibiting lipolysis for generating energy source. Having the above functions, insulin has been used for treating diabetics which require regulation of blood glucose level, however due to its large molecular weight it could not be used for oral administration.
Likewise, macromolecules like insulin and heparin which have a specific bioactivity could not be used for oral administration despite of its physiological usefulness. Therefore, there have been many studies for making appropriate formulation for oral administration of macromolecules. In the previous studies on heparin, cationic cell penetrating materials and hydrophilic or hydrophobic detergents have been administered together for better absorption of heparin (Ross & Toth, 2005). In another study, heparin was administered with N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), but this method could not be used due to the toxicity of a delivery agent (Berkowitz, et al., 1914-1919). Likewise, inventors of the present application have previously developed a method for oral administration of heparin by improving the the above-mentioned properties of heparin through attaching a type of bile acid such as deoxycholic acid monomer or dimer to heparin in a non-site specific manner(U.S. Pat. No. 6,656,922 and Byun et al., Journal of Control Release 120 (2007) 4-10). However, this method has a limitation in improving the interstinal absorption of heparin because as the number of deoxycholic acid moiety increased for improving absoprtion rate, the anti-coagulant activity of heparin was reduced.